Circulatory compromise as a potential mechanism of fatal hepatic failure during long-term selpercatinib therapy: pharmacokinetic and clinical insights.

Selpercatinib is a selective RET inhibitor with established efficacy in RET-altered malignancies; however, data regarding its long-term safety and pharmacokinetic behavior remain limited. We report a case of fatal hepatic failure occurring during prolonged selpercatinib therapy and describe associated clinical and pharmacokinetic findings. A 78-year-old man with RET-mutant medullary thyroid carcinoma received selpercatinib (160 mg twice daily) as second-line therapy following disease progression during vandetanib treatment. After dose interruption and subsequent dose adjustments, the patient achieved a sustained partial response during long-term treatment. Approximately 27 months after selpercatinib initiation, he developed progressive dyspnea, pleural effusion, and severe hepatic dysfunction, ultimately resulting in death. Plasma selpercatinib concentrations were measured during stable disease and later during hepatic decompensation. Pharmacokinetic analysis indicated that drug exposure during the stable treatment period was within the anticipated range, suggesting that elevated drug concentrations observed at the time of hepatic decompensation represented a consequence of impaired clearance rather than a primary cause. These findings implicate circulatory compromise as a potential mediating mechanism and highlight the importance of cardiovascular as well as hepatic monitoring during prolonged selpercatinib therapy. This case highlights a potential indirect mechanism of severe hepatic failure during long-term selpercatinib therapy, in which circulatory compromise-potentially mediated by selpercatinib-associated cardiovascular effects-may have contributed to congestive hepatic decompensation rather than direct drug-induced hepatotoxicity. These findings underscore the importance of integrating cardiovascular surveillance with hepatic monitoring during prolonged selpercatinib treatment.